MKP1 repression is required for the chemosensitizing effects of NF-κB and PI3K inhibitors to cisplatin in non-small cell lung cancer

被引:26
作者
Cortes-Sempere, Maria [1 ,2 ,3 ]
Chattopadhyay, Sharmila [8 ]
Rovira, Ana [6 ,7 ]
Rodriguez-Fanjul, Vanessa [1 ,2 ,3 ]
Belda-Iniesta, Cristobal [4 ]
Tapia, Marian [6 ,7 ]
Cejas, Paloma [4 ]
Machado-Pinilla, Rosario [1 ,2 ,3 ]
Manguan-Garcia, Cristina [1 ,2 ,3 ]
Sanchez-Perez, Isabel [1 ,2 ,3 ]
Nistal, Manuel [5 ]
Moratilla, Carmen [1 ,2 ]
de Castro-Carpeno, Javier [4 ]
Gonzalez-Baron, Manuel [4 ]
Albanell, Joan [6 ,7 ]
Perona, Rosario [1 ,2 ,3 ]
机构
[1] UAM, CSIC, Translat Oncol Unit, Madrid 28029, Spain
[2] UAM, CSIC, Inst Invest Biomed, Madrid 28029, Spain
[3] CIBER Enfermedades Raras CIBERER, Valencia, Spain
[4] Hosp La Paz, Dept Med Oncol, Madrid, Spain
[5] Hosp La Paz, Dept Pathol, Madrid, Spain
[6] Hosp Mar, IMAS, Dept Med Oncol, Barcelona, Spain
[7] Hosp Mar, IMIM, Canc Res Program, PRBB, Barcelona, Spain
[8] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA
关键词
Non-small cell lung cancer; MKP1/DUSP1; siRNA; Jun kinase; NF-kappa B/relB; PI3K/Akt; Cisplatin; Bortezomib; Proteasome; ALPHA PROTEOLYSIS; ACTIVATION; PHOSPHORYLATION; SURVIVAL; APOPTOSIS; PATHWAYS; DEATH; AKT; CHEMOTHERAPY; RESISTANCE;
D O I
10.1016/j.canlet.2009.05.029
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Treatment of non-small cell lung cancer (NSCLC) with cisplatin has a level of antitumor activity still modest. We have shown previously that MKP1/DUSP1 inhibits cisplatin-induced apoptosis in NSCLC cells and is overexpressed in tumors from most patients with stage I-II NSCLC. Here, using different NSCLC cell lines we found that MKP1 and NF-kappa B are differentially expressed. We studied whether targeting MKP1, NF-kappa B or both affects cisplatin-induced cell death. MKP1 is expressed in H460 and H727 cells. H727 and H1299 cells showed constitutive phosphorylation of Akt and increased NF-kappa B activity than did H460 cells. H460-MKP1-siRNA-expressing cells (but not H727-MKP1-siRNA or H1299-MKP1-siRNA cells) exhibit a marked increase in cisplatin response compared with parental cells. Treatment with the PI3K inhibitor LY294002 or the NF-kappa B inhibitor BAY11-7082 enhanced cisplatin antitumor activity in parental H1299 cells but only weakly affected responses of H727 and H460 cells. MKP1-siRNA expression enhanced the chemosensitization effect of LY294002 and BAY11-7082 on H727 and H460 cells. Additionally, NSCLC cell lines with higher NF-kappa B-constitutive activation were the most sensitive to PS-341 (Bortezomib), a non-specific NF-kappa B inhibitor. This finding suggests the proteasome as a suitable strategy in treating NSCLC tumors with high constitutive NF-kappa B activity. Altogether, these results showed that either an activated PI3K/Akt/NF-kappa B pathway and/or high MKP1 was linked to reduced sensitivity to cisplatin in NSCLC cells. Inhibition of NF-kappa B or PI3K potently enhanced cisplatin cytotoxicity in cells with endogenous or genetically induced low MKP1 levels. These findings support the potential improvement in cisplatin responses by co-targeting NF-kappa B or Akt and MKP1. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:206 / 216
页数:11
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